Pulmonary inflammation induced by Pseudomonas aemginosa lipopolysaccharide, phospholipase C, and exotoxin A:: Role of interferon regulatory factor 1

Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. A aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, gamma interferon (IFN-gamma), MIP-1alpha and MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-a and was a weak inducer of IL-1beta, IL-6, macrophage inflammatory protein la (MIP-1alpha), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-gamma. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-alpha, IL-1beta, and IFN-gamma than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1beta and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1alpha and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8(+) and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.